Antifungal activity of acylhydrazone derivatives against sporothrix spp.

Sporotrichosis is an emerging mycosis caused by members of the genus Sporothrix. The disease affects humans and animals, particularly cats, which play an important role in zoonotic transmission. Feline sporotrichosis treatment options include itraconazole (ITC), potassium iodide, and amphotericin B, drugs usually associated with deleterious adverse reactions and refractoriness in cats, especially when using ITC. Thus, affordable, nontoxic, and clinically effective anti-Sporothrix agents are needed. Recently, acylhydrazones (AH), molecules targeting vesicular transport and cell cycle progression, exhibited a potent antifungal activity against several fungal species and displayed low toxicity compared to the current drugs. In this work, the AH derivatives D13 and SB-AF- 1002 were tested against Sporothrix schenckii and Sporothrix brasiliensis. MICs of 0.12 to 1mg/ml were observed for both species in vitro. D13 and SB-AF-1002 showed an additive effect with itraconazole. Treatment with D13 promoted yeast disruption with the release of intracellular components, as confirmed by transmission electron microscopy of S. brasiliensis exposed to the AH derivatives. AH-treated cells displayed thickening of the cell wall, discontinuity of the cell membrane, and an intense cytoplasmic degeneration. In a murine model of sporotrichosis, treatment with AH derivatives was more efficient than ITC, the drug of choice for sporotrichosis. Our results expand the antifungal broadness of AH derivatives and suggest that these drugs can be exploited to combat sporotrichosis.